Cancer is a serious health issue all around the world. Despite recent advancements made in treating cancers, it is often observed that with exceptions, a cancer treatment fails to cure a patient. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. For example, after several cycles of therapy, some tumor cells become resistant to the therapeutic agent, which results in a loss of response to further therapy.
Head and neck squamous cell carcinoma (HNSCC), which comprises the cancers originating from the oral cavity, oropharynx, larynx, and hypopharynx, is one of the major cancers worldwide. In recent years, targeting epidermal growth factor receptor (EGFR) has become a major strategy for combating late-stage HNSCC because EGFR overexpression is observed in approximately 90% of HNSCC cases and is associated with an unfavorable outcome (Grandis J. R. et al., Cancer Res 53:3579-84 (1993), Chung C. H. et al., J Clin Oncol 24: 4170-6 (2006)).
Pivotal clinical studies demonstrated that cetuximab, a humanized IgG1 monoclonal antibody against the extracellular domain of EGFR, is effective in advanced HNSCC patients when combined with radiation or chemotherapy (Vormorken J. B. et al., N Engl J Med 359:1116-27 (2008)). Therefore, cetuximab has been regarded as a major treatment for advanced or recurrent/metastatic HNSCC. However, the improvement in survival afforded by cetuximab is not as extensive as expected (Bonner J. A. et al., Lancet Oncol 11:21-8 (2010)). Notably, although the initial response rate to cetuximab in HNSCC is high, most of the patients eventually develop resistance to cetuximab, i.e., acquired resistance (Rabinowits G. et al., Oral Oncol 48:1085-9 (2012)), and the efficacy of cetuximab as second-line therapy after chemotherapy failure is far behind its performance in first-line treatment.
Overcoming acquired resistance to cetuximab is of utmost importance for cancer, such as advanced HNSCC.